Use of anti-oestrogens as male contraceptives

ABSTRACT

This invention describes the use of antiestrogens (aromatase inhibitors, estrogen receptor antagonists) for the production of pharmaceutical agents for male birth control.

[0001] This invention relates to the use of antiestrogens for theproduction of pharmaceutical agents for male birth control.

[0002] In the more narrow sense, antiestrogens comprise the class ofsubstances of compounds that can displace estrogens from theirrespective receptors (estrogen receptor antagonists) and, in the broadersense, also the compounds that prevent the synthesis of estrogens fromtheir metabolic precursors in the organism—androgenic compounds with a3-keto-4-ene steroid structure—by inhibiting the enzyme aromatase(aromatase inhibitors). These two groups, which in final analysisinhibit the biological action of estrogens, fall into the category ofboth steroidal and non-steroidal compounds in each case. In addition tothe so-called pure antiestrogens, such as, e.g.,7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17β-diol,those compounds that, in addition to their antagonistic action, alsohave considerable agonistic, i.e., estrogenic, action, are among thecompetitive antiestrogens. The most prominent representative of thelatter is tamoxifen.

[0003] There are already a considerable number of indications for whichantiestrogens can be used. The best-known example is the clinicaltreatment of breast cancer with tamoxifen, which has been practiced fora long time.

[0004] The use of antiestrogens (centchroman) for female contraceptionin humans is also described (Nittyanand, S., Kamboj VP [1992]Centchroman: Contraceptive Efficacy and Safety Profile. InternationalConference on Fertility Regulation, November 5-8, 1992 Bombay, India,Programs and Abstracts). At effective dosages, however, undesirableside-effects such as, for example, osteoporotic changes, occur, whichcan be attributed to the systemic action of antiestrogens. Estrogendeprivation, which can occur after long-term treatment with anantiestrogen, limits at least their regular use for femalecontraception.

[0005] Finally, DE-A 42 13 005 describes the use of aromatase inhibitorsfor contraception in female primates of reproductive age at a dosage, inwhich the menstrual cycle of the female primate remains basicallyunaffected. In this case, the absolute level of the daily doses that arerequired for contraceptive action depends completely on the type ofaromatase inhibitor that is used. For highly active aromataseinhibitors, the daily doses are generally between about 0.05 and about30 mg. In the case of less active aromatase inhibitors, the daily dosescan also be higher.

[0006] For male birth control, until now only condoms and vasectomy havebeen available. The former are only conditionally suitable both in termsof acceptance and in contraceptive reliability; vasectomies aregenerally irreversible with respect to fertility. A hormonalcontraceptive that would be comparable to the oral contraceptives forwomen with respect to effectiveness, reliability, type of use, andacceptance was previously not in the offing. A further major advantageof hormonal contraception in women is its reversibility.

[0007] A summary of the current state of efforts for the development ofa contraceptive for men is found in U. F. Habenicht in “Sitzungsberichteder Gesellschaft Naturforschender Freunde zu Berlin [Minutes of theSociety of Friends of Natural Science in Berlin],” Volume 31, 1991, pp.101-116.

[0008] Neither direct inhibition of spermatogenesis by variousalkylating agents or the gossypols that have become known as “Chinapills” nor indirect inhibition of spermatogenesis by blocking thehypophyseal-hypothalamic system by using testosterone derivatives ofLHRH analogues (agonists or antagonists) in combination withtestosterone derivatives or with a combination of an androgen with agestagen has yet produced the desired success.

[0009] In final analysis, the described attempts do not meet at leastone of the two most important requirements of a modern contraceptive formen, namely the requirement for method reversibility and the lowestpossible potential for side-effects.

[0010] In addition, the use of antigestagens (competitive progesteronereceptor antagonists) for male birth control was also described (DE-A-4039 561.8).

[0011] In treating male bonnet monkeys with RU 486(11β-[(4-N,N-dimethylamino)-phenyl]-17β-hydroxy-17α-propinyl-4,9(10)-estradien-3-one,reduction of ejaculation weight, sperm count per ejaculation, reductionin sperm mobility, morphologic anomalities of sperm, and aloss/inhibition of acrosomes were observed.

[0012] The object of this invention is to provide a pharmaceutical agentfor reversible control of male fertility which, in comparison to thealready proposed pharmaceutical agents for this indication, is toexhibit fewer side-effects or better manageability.

[0013] This object is achieved by using antiestrogens for the productionof pharmaceutical agents for male birth control.

[0014] It has now been found that antiestrogens, surprisingly enough,alter the acrosomal status of sperm: Thus, under the influence ofantiestrogens, an incipient acrosomal reaction is observed. At the sametime, the motility of the sperm is impaired by the antiestrogens.

[0015] The early induction of acrosomal reaction and the limitation ofsperm motility may suggest that the latter are incapable offertilization.

[0016] On the other hand, various parameters of the male sexualfunctions remain unaffected by antiestrogens: the organ weight of themale reproductive tract and the sperm concentration are not altered.

[0017] Thus, reversible inhibition of sperm functions, which areessential for successful fertilization, is produced by theantiestrogens.

[0018] These results are all the more astonishing as antiestrogens, suchas, e.g., tamoxifen or clomiphene, have been used in certain malepatients to correct fertility disorders [Acosta et al., Fertil. Steril.55, pp. 1150-6, (1991)]. As a result, a locally increased estrogenconcentration that is assumed to be present in the testes is to becounteracted, which possibly could be the cause of fertility disorders.In these patients, two active components of the antiestrogens used areat work: on the one hand, the antiestrogenic action per se, and on theother the endogenic testosterone increase due to the feedback mechanism(counterregulation).

[0019] The above-described properties of antiestrogens were obtained intests that were performed with the ICI-antiestrogen7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17β-diolon normal adult male rats.

[0020] This compound can be regarded as a standard compound for allcompounds of this class of substances.

[0021] The test design and the results are described in the list below:Rats normal male animals, weight about 200 g group treated with ICI7α-[9- 2.5 mg/kg in a 0.2 ml vehicle (4,4,5,5,5- subcutaneously on anoily base pentafluoropentylsulfinyl)- (benzylbenzoate/castor oil)nonyl]-estra-1,3,5(10)-triene- 3,17β-diol (n = 6; number of animals)Vehicle control (n = 6; number 0.2 ml of vehicle 1 × daily of animals)Period of treatment 28 days Determination of the organ seminal vesicles,prostate, weight of the male testicles, epididymis reproductive tractand histology Extraction of sperm Extraction from the epididymis(epididymal sperm) Determination of: -- motility -- number -- acrosomalstate (corresponding to the WHO-rich lines)

[0022] Observations regarding the organ weight of the male reproductivetract and sperm properties:

[0023] 1. No effects on the weight or histology of the organs studied

[0024] 2. Inhibition of motility

[0025] 3. Induction of an early incipient acrosomal reaction.

[0026] These observations clearly show that antiestrogens are suitablefor the production of pharmaceutical agents for male birth control.

[0027] As compounds that have an antiestrogenic action, both competitiveantiestrogens (estrogen receptor antagonists) and aromatase inhibitorsaccording to the invention are suitable. Estrogen receptor antagonistsand aromatase inhibitors according to this invention can be derived fromboth steroids or non-steroidal compounds. Compounds that have anantiestrogen action, in the broadest sense, are to be defined accordingto this invention only as those compounds that have the most selectiveaction possible, i.e., that basically inhibit only the action ofestrogens and/or reduce their concentration.

[0028] The estrogen receptor antagonists have a competitive action, bydisplacing estrogens from the receptor, while aromatase inhibitorsinhibit the biosynthesis of estrogens. According to this invention,compounds of the aminoglutethimide type, i.e.,3-(4-aminophenyl)piperidine-2,6-diones that are alkylated in 3-position,etc., which in addition to the estrogen level also exert a reducingaction on other sexual hormone serum concentrations, are not suitable ascompounds that have an antiestrogenic action.

[0029] As non-steroidal estrogen receptor antagonists, there can bementioned, for example:

[0030]Tamoxifen=(Z)-2-[p-(1,2-diphenyl-1-butenyl)-phenoxy]-N,N-dimethylethylamine,

[0031]nafoxidine=1-2-[4-(6-methoxy-2-phenyl-3,4-dihydro-1-naphthyl)-phenoxy]-ethylpyrrolidine,hydrochloride,

[0032] Mer25=1-[p-(2-diethylaminoethoxy)-phenyl]-2-(p-methoxyphenyl)-1-phenylethanol

[0033]raloxifene=6-hydroxy-2-(p-hydroxyphenyl)benzo[b]thien-3-yl-p-(2-piperidino-ethoxy)phenylketone, hydrochloride;

[0034] centchromane

[0035] other compounds of 1,1,2-triphenylbut-1-ene type, especially1,1-bis-(3′-acetoxyphenyl)-2-phenyl-but-1-ene [J. Cancer Res. Clin.Oncol., (1986), 112, pp. 119-124];

[0036] also suitable as steroidal estrogen receptor antagonists are, forexample:

[0037] 11α-methoxy-17α-ethinyl-1,3,5(10)-estratriene-3,17β-diol and16β-ethylestradiol,N-n-butyl-N-methyl-11-(3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl)-undecanamideand

[0038]7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17β-diol.

[0039] As aromatase inhibitors, all compounds are suitable that aresuitable as substrates for aromatase, such as, for example, the1-methyl-androsta-1,4-diene-3,17-dione (atamestane) that is described inGerman Laid-Open Specification 33 22 285), the testolactone(17α-oxa-D-homoandrost-1,4-diene-3,17-dione) that is described inJournal of Clinical Endocrinology and Metabolism, 49, 672 (1979), thecompounds that are described in “Endocrinology” 1973, Vol. 92, No. 3,page 874:

[0040] androsta-4,6-diene-3,17-dione,

[0041] androsta-4,6-dien-17β-ol-3-one-acetate,

[0042] androsta-1,4,6-triene-3,17-dione,

[0043] 4-androstene-19-chloro-3,17-dione,

[0044] 4-androstene-3,6,17-trione,

[0045] the 19-alkynylated steroids that are described in GermanLaid-Open Specification 31 24 780,

[0046] the 10-(1,2-propadienyl)-steroids that are described in GermanLaid-Open Specification 31 24 719,

[0047] the 19-thio-androstane derivatives that are described in EuropeanPatent Application, Publication No. 100 566,

[0048] the 4-androsten-4-ol-3,17-dione that is described in“Endocrinology” 1977, Vol. 100, No. 6, page 1684 and U.S. Pat. No.4,235,893 and its esters,

[0049] the 1-methyl-15α-alkyl-androsta-1,4-diene-3,17-diones that aredescribed in German Laid-Open Specification 35 39 244,

[0050] the 10β-alkinyl-4,9(11)-estradiene derivatives that are describedin German laid-open specification 36 44 358 and the1,2β-methylene-6-methylene-4-androstene-3,17-dione that is described inEuropean Patent Application 0 250 262.

[0051] As non-steroidal aromatase inhibitors, for example,[4-(5,6,7,8-tetrahydroimidazo[1,5α]-pyridin-5-yl)benzonitrile-mono-hydrochloride] (Cancer Res., 48,pp. 834-838, 1988) and the cycloalkylenazoles that are described inEP-A-0 411 735 can be mentioned. The best-known representative of thelast-mentioned compounds is the pentrozole that was already mentioned.

[0052] In addition, the compounds that were specifically mentioned asaromatase inhibitors in DE-A 42 13 005 can be used within the scope ofthis invention.

[0053] This list is not exhaustive; other antiestrogens that aredescribed in the above-mentioned publications, as well as those from thepublications that are not mentioned here, are also suitable.

[0054] The antiestrogens can be used according to this invention forsuppressing male fertility according to different treatment schemes.

[0055] 1. Intermittent treatment One-time daily to weekly oral treatmentover 4-12 months. Then: a treatment-free interval of 3-5 months. Afterthat, renewed treatment as above.

[0056] 2. Continuous treatment One-time daily oral administration ororal administration at two-day to at most seven-day regular intervals oradministration of depot formulations at regular intervals (e.g., 1× permonth, 1× per quarter, etc.).

[0057] To produce a pharmaceutical agent for male birth control, theantiestrogens are used in a daily amount of 0.1 to 100 mg p.o. tamoxifenor an equivalent-action amount of another antiestrogen.

[0058] In the case where a depot formulation is used for the productionof the pharmaceutical agent according to the invention, this depotformulation is selected in such a way that the daily rate of release ofantiestrogen is 0.1 to 100 mg of tamoxifen or an equivalent-actionamount of another antiestrogen.

[0059] Equivalent-action amounts of other antiestrogens, i.e., amountsthat correspond to the indicated amount of tamoxifen for the inhibitionof male fertility, can be determined, for example, in the uterusgrowth-inhibiting test after estrogen stimulation.

[0060] In the case of the production of oral dosage units, theformulation of antiestrogens for the purposes of this invention is donecompletely analogously to the already known use of tamoxifen (Eur. J.Cancer Clin. Oncol., 1985, 21, 985 and J. S. Patterson, “10 Years ofTamoxifen in Breast Cancer” in Hormonal Manipulation of Cancer;Peptides, Growth Factors and New (Anti)steroidal Agents, Raven Press,New York (1987)).

[0061] For the antiestrogen to be used in a depot formulation, it can beprepared as a microcrystal suspension, as an oily solution, or in theform of a vehicle that contains active ingredients (transdermal system).

[0062] The following examples are used to give a more detailedexplanation of the invention.

EXAMPLE 1

[0063]20.0 mg of tamoxifen (antiestrogen with agonistic partial action)

[0064] 140.0 mg of lactose

[0065] 55.0 mg of corn starch

[0066] 2.5 mg of poly-N-vinylpyrrolidone 25

[0067]2.0 mg of aerosil

[0068] 0.5 ma of magnesium stearate

[0069] 220.0 mg total weight of the tablet, which is produced in theusual way on a tablet press. The active ingredient according to theinvention optionally also can be pressed with respectively half theabove-indicated additives separately into a two-layer tablet.

EXAMPLE 2

[0070]5.0 mg of7β-[9-(4,4,5,5,5-Pentafluoropentylsulfinyl)-nonyl]estra-1,3,5(10)-triene-3,17β-diol(pure antiestrogen)

[0071] 150.0 mg of lactose

[0072] 60.0 mg of corn starch

[0073] 2.5 mg of poly-N-vinylpyrrolidone 25

[0074]2.0 mg of aerosil

[0075] 0.5 mg of magnesium stearate

[0076] 220.0 mg total weight of the tablet, which is produced in theusual way on a tablet press. The active ingredient according to theinvention optionally also can be pressed with respectively half theabove-indicated additives separately into a two-layer tablet.

EXAMPLE 3

[0077]0.2 mg of5-[Cyclopentylidene-(1-imidazolyl)-methyl]-thiophene-2-carbonitrile(aromatase inhibitor-pentrozole)

[0078] 160.0 mg of lactose

[0079] 54.8 mg of corn starch

[0080] 2.5 mg of poly-N-vinylpyrrolidone 25

[0081]2.0 mg of aerosil

[0082] 0.5 mg of magnesium stearate

[0083] 220.0 mg total weight of the tablet, which is produced in theusual way on a tablet press. The active ingredient according to theinvention optionally also can be pressed with respectively half theabove-indicated additives separately into a two-layer tablet.

1. Use of antiestrogens for the production of pharmaceutical agents formale birth control.
 2. Use of estrogen receptor antagonists according toclaim 1 .
 3. Use of aromatase inhibitors according to claim 1 .
 4. Useof tamoxifen according to claim 2 .
 5. Use of7β-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17β-diolaccording to claim 2 .
 6. Use of atamestane according to claim 3 . 7.Use of pentrozole according to claim 3 .